Renin-angiotensin system is involved in embryonic emergence of hematopoietic stem/progenitor cells

Abstract

Angiotensin‐converting enzyme (ACE), a key element of the renin‐angiotensin system (RAS), has recently been identified as a new marker of both adult and embryonic human hematopoietic stem/progenitor cells (HSPCs). However, whether a full renin‐angiotensin pathway is locally present during the hematopoietic emergence is still an open question. In the present study, we show that this enzyme is expressed by hematopoietic progenitors in the developing mouse embryo. Furthermore, ACE and the other elements of RAS—namely angiotensinogen, renin, and angiotensin II type 1 (AT1) and type 2 (AT2) receptors—are expressed in the paraaortic splanchnopleura (P‐Sp) and in its derivative, the aorta‐gonad‐mesonephros region, both in human and mouse embryos. Their localization is compatible with the existence of a local autocrine and/or paracrine RAS in these hemogenic sites. in vitro perturbation of the RAS by administration of a specific AT1 receptor antagonist inhibits almost totally the generation of blood CD45‐positive cells from dissected P‐Sp, implying that angiotensin II signaling is necessary for the emergence of hematopoietic cells. Conversely, addition of exogenous angiotensin II peptide stimulates hematopoiesis in culture, with an increase in the number of immature c‐Kit+CD41+CD31+CD45+ hematopoietic progenitors, compared to the control. These results highlight a novel role of local‐RAS during embryogenesis, suggesting that angiotensin II, via activation of AT1 receptor, promotes the emergence of undifferentiated hematopoietic progenitors.

Murine AGM single-cell profiling identifies a continuum of hemogenic endothelium differentiation marked by ACE

“…ACE converts angiotensin-1 into angiotensin-2, which in turn activates angiotensin-2 receptors (AT1, AT2). 96 Two recent reports 97,98 have implicated the endothelin-renin-angiotensin system (which includes ACE) in AGM hematopoiesis. In human and mouse, Atgr1 (coding for AT1) expression has been detected in subaortic DA cells.…”

CDX2 regulates ACE expression in blood development and leukemia cells

“…At early stages of murine development (embryonic day 9 [E9]), both proteins were synthetized in the extraembryonic YS endoderm and in the intraembryonic P-Sp (including the gut endoderm): the region endowed with hematopoietic ability 20,21 (supplemental Figure 1). Because our previous observations indicated ACE as a marker of HSCs in the AGM region, 3,4 we focused on CDX2 at this site. By reverse transcription-polymerase chain reaction (RT-PCR), CDX2 transcripts were detected in the AGM region that also expressed ACE (supplemental Figure 2).…”

“…This opens new perspectives for understanding the deleterious effect exerted by CDX2 upon abnormal reexpression in leukemia through the proliferative effect exerted by AngII on hematopoietic cell emergence and growth. 4,25…”

“…3 In the embryo, ACE identifies HSCs associated with the ventral side of the aortic endothelium (in the AGM region) and of vitelline and umbilical arteries, both in humans 3 and mice. 4 ACE is a key component of the renin-angiotensin system (RAS), catalyzing the production of angiotensin II (AngII), 5 which we have recently shown to be involved in hematopoietic emergence during ontogeny. 4 ACE overexpression, leading to AngII increase, has also been reported in the BM of patients with acute myeloid leukemia (AML), influencing malignancy 6,7 ; however, its mechanisms of regulation are still unknown.…”

“…4 ACE is a key component of the renin-angiotensin system (RAS), catalyzing the production of angiotensin II (AngII), 5 which we have recently shown to be involved in hematopoietic emergence during ontogeny. 4 ACE overexpression, leading to AngII increase, has also been reported in the BM of patients with acute myeloid leukemia (AML), influencing malignancy 6,7 ; however, its mechanisms of regulation are still unknown. 8 The caudal-related homeobox gene 2 (CDX2) encodes an important transcription factor involved in tissue expansion and patterning of the posterior embryo.…”